Factors Associated with Fatigue in COVID-19 ICU Survivors.

PURPOSE: Approximately 30% of people infected with COVID-19 require hospitalization and 20% of them are admitted to an intensive care unit (ICU). Most of these patients experience symptoms of fatigue weeks post-ICU, so understanding the factors associated with fatigue in this population is crucial. METHODS: Fifty-nine patients [38-78 yr] hospitalized in ICU for COVID-19 infection for 32 [6-80] days including 23 [3-57] days of mechanical ventilation, visited the laboratory on two separate occasions. The first visit occurred 52 ± 15 days after discharge and was dedicated to questionnaires, blood sampling and cardiopulmonary exercise testing, while measurements of the knee extensors neuromuscular function and performance fatigability were performed in the second visit 7 ± 2 days later. RESULTS: Using the FACIT-F questionnaire, 56% of patients were classified as fatigued. Fatigued patients had worse lung function score than non- fatigued (i.e. 2.9 ± 0.8 L vs 3.6 ± 0.8 L; 2.4 ± 0.7 l vs 3.0 ± 0.7 L for forced vital capacity and forced expiratory volume in one second, respectively) and forced vital capacity was identified as a predictor of being fatigued. Maximal voluntary activation was lower in fatigued patients than non-fatigued patients (82 ± 14% vs 91 ± 3%) and was the only neuromuscular variable that discriminated between fatigued and non-fatigued patients. Patient-reported outcomes also showed differences between fatigued and non-fatigued patients for sleep, physical activity, depression and quality of life (p < 0.05). CONCLUSIONS: COVID-19 survivors showed altered respiratory function 4 to 8 weeks after discharge, that was further deteriorated in fatigued patients. Fatigue was also associated with lower voluntary activation and patient-reported impairments (i.e. sleep satisfaction, quality of life or depressive state). The present study reinforces the importance of exercise intervention and rehabilitation to counteract cardiorespiratory and neuromuscular impairments of COVID-19 patients admitted in ICU, especially individuals experiencing fatigue.

Benefits of Individualized Training in Fatigued Patients with Multiple Sclerosis.

INTRODUCTION: Chronic fatigue is the most common and debilitating symptom in people with multiple sclerosis (PwMS). Recently, exercise has been proven to alleviate chronic fatigue and improve physical functions. Tailoring the training intervention to the potential fatigue causes could optimize the beneficial effects of training on fatigue. The objective of this study was to compare the effectiveness of an individualized (IND) vs a traditional (TRAD) exercise intervention in reducing chronic fatigue. METHODS: Twenty-nine PwMS with high chronic fatigue were randomly assigned to 12 weeks of either a TRAD or IND exercise intervention. TRAD comprised aerobic and resistance exercises according to the guidelines for PwMS. IND specifically addressed identified individual weaknesses. Participants visited the laboratory before and after training for the following assessments: patient reported outcomes (fatigue, quality of life, depression questionnaires), incremental cycling test (V̇O 2peak ), and cycling fatigue test (maximal voluntary contraction, MVC; rating of perceived exertion, RPE). RESULTS: Similar improvements in fatigue, depression and quality of life were observed between groups (p > 0.05). Compared to TRAD, IND induced a significant greater increase in V̇O 2peak (+21.0 ± 13.9 vs 6.8 ± 11.5%, p < 0.05) and a greater reduction in RPE at a given submaximal intensity (-30.3 ± 18.9 vs -12.1 ± 20.4%, p < 0.001), whereas MVC increased similarly in both groups (p > 0.05). CONCLUSIONS: Although tailored exercise improved similarly fatigue and other subjective parameters (depression, quality of life, sleep quality) compared to than traditional exercise interventions, prescribing an individualized intervention led to greater improvement in V̇O 2peak (but not maximal strength) and perception of effort. This may have positive functional consequences for patients.

Alteration of skeletal muscle energy metabolism assessed by 31 P MRS in clinical routine: Part 2. Clinical application.

In this second part of a two-part paper, we intend to demonstrate the impact of the previously proposed advanced quality control pipeline. To understand its benefit and challenge the proposed methodology in a real scenario, we chose to compare the outcome when applying it to the analysis of two patient populations with significant but highly different types of fatigue: COVID-19 and multiple sclerosis (MS). 31 P-MRS was performed on a 3 T clinical MRI, in 19 COVID-19 patients, 38 MS patients, and 40 matched healthy controls. Dynamic acquisitions using an MR-compatible ergometer ran over a rest (40 s), exercise (2 min), and a recovery phase (6 min). Long and short TR acquisitions were also made at rest for T1 correction. The advanced data quality control pipeline presented in Part 1 is applied to the selected patient cohorts to investigate its impact on clinical outcomes. We first used power and sample size analysis to estimate objectively the impact of adding the quality control score (QCS). Then, comparisons between patients and healthy control groups using the validated QCS were performed using unpaired t tests or Mann-Whitney tests (p < 0.05). The application of the QCS resulted in increased statistical power, changed the values of several outcome measures, and reduced variability (standard deviation). A significant difference was found between the T1PCr and T1Pi values of MS patients and healthy controls. Furthermore, the use of a fixed correction factor led to systematically higher estimated concentrations of PCr and Pi than when using individually corrected factors. We observed significant differences between the two patient populations and healthy controls for resting [PCr]-MS only, [Pi ], [ADP], [H2 PO4 - ], and pH-COVID-19 only, and post-exercise [PCr], [Pi ], and [H2 PO4 - ]-MS only. The dynamic indicators τPCr , τPi , ViPCr , and Vmax were reduced for COVID-19 and MS patients compared with controls. Our results show that QCS in dynamic 31 P-MRS studies results in smaller data variability and therefore impacts study sample size and power. Although QCS resulted in discarded data and therefore reduced the acceptable data and subject numbers, this rigorous and unbiased approach allowed for proper assessment of muscle metabolites and metabolism in patient populations. The outcomes include an increased metabolite T1 , which directly affects the T1 correction factor applied to the amplitudes of the metabolite, and a prolonged τPCr , indicating reduced muscle oxidative capacity for patients with MS and COVID-19.

Alteration of skeletal muscle energy metabolism assessed by phosphorus-31 magnetic resonance spectroscopy in clinical routine, part 1: Advanced quality control pipeline.

Implementing a standardized phosphorus-31 magnetic resonance spectroscopy (31 P-MRS) dynamic acquisition protocol to evaluate skeletal muscle energy metabolism and monitor muscle fatigability, while being compatible with various longitudinal clinical studies on diversified patient cohorts, requires a high level of technicality and expertise. Furthermore, processing data to obtain reliable results also demands a great degree of expertise from the operator. In this two-part article, we present an advanced quality control approach for data acquired using a dynamic 31 P-MRS protocol. The aim is to provide decision support to the operator to assist in data processing and obtain reliable results based on objective criteria. We present here, in part 1, an advanced data quality control (QC) approach of a dynamic 31 P-MRS protocol. Part 2 is an impact study that will demonstrate the added value of the QC approach to explore data derived from two clinical populations that experience significant fatigue, patients with coronavirus disease 2019 and multiple sclerosis. In part 1, 31 P-MRS was performed using 3-T clinical MRI in 175 subjects from clinical and healthy control populations conducted in a University Hospital. An advanced data QC score (QCS) was developed using multiple objective criteria. The criteria were based on current recommendations from the literature enriched by new proposals based on clinical experience. The QCS was designed to indicate valid and corrupt data and guide necessary objective data editing to extract as much valid physiological data as possible. Dynamic acquisitions using an MR-compatible ergometer ran over a rest (40 s), exercise (2 min), and a recovery phase (6 min). Using QCS enabled rapid identification of subjects with data anomalies, allowing the user to correct the data series or reject them partially or entirely, as well as identify fully valid datasets. Overall, the use of the QCS resulted in the automatic classification of 45% of the subjects, including 58 participants who had data with no criterion violation and 21 participants with violations that resulted in the rejection of all dynamic data. The remaining datasets were inspected manually with guidance, allowing acceptance of full datasets from an additional 80 participants and recovery phase data from an additional 16 subjects. Overall, more anomalies occurred with patient data (35% of datasets) compared with healthy controls (15% of datasets). In conclusion, the QCS ensures a standardized data rejection procedure and rigorous objective analysis of dynamic 31 P-MRS data obtained from patients. This methodology contributes to efforts made to standardize 31 P-MRS practices that have been underway for a decade, with the goal of making it an empowered tool for clinical research.

A Comprehensive Evaluation of Multiple Sclerosis-Related Fatigue with a Special Focus on Fatigability.

INTRODUCTION: Fatigue is the most common and disabling symptom in multiple sclerosis (MS), being reported by 55% to 78% of patients with MS (PwMS). Etiology of MS-related fatigue remains poorly understood, but an increased neuromuscular fatigability (i.e., greater loss of torque during exercise) could contribute to this phenomenon. This study aimed to characterize the correlates of MS-related fatigue in PwMS using a comprehensive group of physiological and psychosocial measures, with a particular focus on fatigability. METHODS: Forty-two relapsing-remitting PwMS and 20 healthy subjects were recruited. PwMS were assigned in two groups (high (HF) and low (LF) fatigue) based on two fatigue questionnaires (Fatigue Severity Scale and Modified Fatigue Impact Scale). The main outcomes of this study are derived from incremental cycling completed to task failure (i.e., inability to pedal around 60 rpm). Maximal voluntary contraction (MVC), rating of perceived exertion, and central and peripheral parameters measured using transcranial magnetic and peripheral nerve stimulation were assessed in the knee extensor muscles before, during, and after the fatiguing task. Other potential correlates of fatigue were also tested. RESULTS: MVC torque decreased to a greater extent for the HF group than LF group after the third common stage of the incremental fatiguing exercise (-15.7% ± 6.6% vs -5.9% ± 13.0%, P < 0.05), and this occurred concurrently with a higher rating of perceived exertion for HF (11.8 ± 2.5 vs 9.3 ± 2.6, P < 0.05). Subjective parameters (depression, quality of life) were worse for HF compared with LF and healthy subjects ( P < 0.001). Moreover, MVC torque loss at the final common stage and maximal heart rate explained 29% of the variance of the Modified Fatigue Impact Scale. CONCLUSIONS: These results provide novel insight into the relationship between MS-related fatigue and fatigability among PwMS. The HF group exhibited greater performance fatigability, likely contributing to a higher perceived exertion than the LF group when measured during a dynamic task.

How is neuromuscular fatigability affected by perceived fatigue and disability in people with multiple sclerosis?

Whereas fatigue is recognized to be the main complaint of patients with multiple sclerosis (PwMS), its etiology, and particularly the role of resistance to fatigability and its interplay with disability level, remains unclear. The purposes of this review were to (i) clarify the relationship between fatigue/disability and neuromuscular performance in PwMS and (ii) review the corticospinal and muscular mechanisms of voluntary muscle contraction that are altered by multiple sclerosis, and how they may be influenced by disability level or fatigue. Neuromuscular function at rest and during exercise are more susceptible to impairement, due to deficits in voluntary activation, when the disability is greater. Fatigue level is related to resistance to fatigability but not to neuromuscular function at rest. Neurophysiological parameters related to signal transmission such as central motor conduction time, motor evoked potentials amplitude and latency are affected by disability and fatigue levels but their relative role in the impaired production of torque remain unclear. Nonetheless, cortical reorganization represents the most likely explanation for the heightened fatigability during exercise for highly fatigued and/or disabled PwMS. Further research is needed to decipher how the fatigue and disability could influence fatigability for an ecological task, especially at the corticospinal level.

Performance fatigability during isometric vs. concentric quadriceps fatiguing tasks in men and women.

In the present study, we aimed to provide a robust comparison of the fatigability of the knee extensors following isometric (ISO) and concentric (CON) tasks. Twenty young adults (25 ± 4 yr, 10 women) randomly performed the ISO and CON quadriceps intermittent fatigue test, consisting of ten (5 s on/5-s off, ISO) or one-hundred (0.5-s on/0.5-s off, CON) contractions with 10 % increments per stage until exhaustion. Performance fatigability was quantified as maximal isometric (MVIC) and concentric (MVCC) torque loss. Voluntary activation and contractile function (peak-twitch) were investigated using peripheral nerve stimulation. Number of stages (6.2 ± 0.7 vs. 4.9 ± 0.8; P < 0.001) and torque-time integral (20,166 ± 7,821 vs. 11,285 ± 4,933 Nm.s; P < 0.001) were greater for ISO than CON. MVIC, MVCC and voluntary activation decreased similarly between sessions (P > 0.05) whereas peak-twitch amplitude decreased more for CON (P < 0.001). The number of contractions was similar across sexes (ISO: men = 62 ± 8, women = 61 ± 5; CON: men = 521 ± 67, women = 458 ± 76, P > 0.05). MVCC was more reduced in women for both sessions (all P < 0.05), while MVIC loss was similar between sexes. We concluded that, despite greater torque-time integral and duration for ISO, both sessions induced a similar performance fatigability at exhaustion. Contractile function was more altered in CON. Finally, sex-related difference in fatigability depends on the contraction mode used during testing.

Prevalence of fatigue and its explicative variables among people with multiple sclerosis.

BACKGROUND: Fatigue is the most prevalent symptom among people with multiple sclerosis (PwMS). Although exercise effectively reduces fatigue, the relationship between daily physical activity and fatigue has only recently been demonstrated. OBJECTIVE: The aim of this study was to evaluate the prevalence of fatigue and to understand the relationship with several variables in French PwMS. METHODS: Data were collected from 191 PwMS using Modified Fatigue Impact Scale (MFIS) and Fatigue Severity Scale (FSS) for fatigue, and the Godin Leisure-Time Exercise Questionnaire (GLTEQ) for physical activity. RESULTS: 110 PwMS (57%), 35 PwMS (18%) and 46 PwMS (24%) were considered as fatigued, non-fatigued and in the grey zone, respectively. Greater physical activity was observed in non-fatigued PwMS (20.2±19.8) compared to fatigued PwMS (12.5±14.1). FSS and MFIS scores were associated with physical activity (r = -0.28 and r = -0.25, respectively, p < 0.05). Using multivariate analysis, disability, physical activity and being unemployed explained 21% of the variance of the MFIS. CONCLUSIONS: The present study confirms that physical activity and fatigue are associated. Disability and unemployment status should also to be consider when assessing fatigue. Activity-oriented health policies should be redesigned to improve fatigue among PwMS.

Cardiorespiratory Fitness and Neuromuscular Function of Mechanically Ventilated ICU COVID-19 Patients.

OBJECTIVES: The aim of the current study was to investigate the level of cardiorespiratory fitness and neuromuscular function of ICU survivors after COVID-19 and to examine whether these outcomes are related to ICU stay/mechanical ventilation duration. DESIGN: Prospective nonrandomized study. SETTING: Patients hospitalized in ICU for COVID-19 infection. PATIENTS: Sixty patients hospitalized in ICU (mean duration: 31.9 ± 18.2 d) were recruited 4-8 weeks post discharge from ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients visited the laboratory on two separate occasions. The first visit was dedicated to quality of life questionnaire, cardiopulmonary exercise testing, whereas measurements of the knee extensors neuromuscular function were performed in the second visit. Maximal oxygen uptake (V o2 max) was 18.3 ± 4.5 mL·min -1 ·kg -1 , representing 49% ± 12% of predicted value, and was significantly correlated with ICU stay/mechanical ventilation (MV) duration ( R = -0.337 to -0.446; p < 0.01 to 0.001), as were maximal voluntary contraction and electrically evoked peak twitch. V o2 max (either predicted or in mL· min -1 ·kg -1 ) was also significantly correlated with key indices of pulmonary function such as predicted forced vital capacity or predicted forced expiratory volume in 1 second ( R = 0.430-0.465; p ≤ 0.001) and neuromuscular function. Both cardiorespiratory fitness and neuromuscular function were correlated with self-reported physical functioning and general health status. CONCLUSIONS: V o2 max was on average only slightly above the 18 mL·min -1 ·kg -1 , that is, the cut-off value known to induce difficulty in performing daily tasks. Overall, although low physical capacities at admission in ICU COVID-19 patients cannot be ruled out to explain the association between V o2 max or neuromuscular function and ICU stay/MV duration, altered cardiorespiratory fitness and neuromuscular function observed in the present study may not be specific to COVID-19 disease but seem applicable to all ICU/MV patients of similar duration.

Neuromuscular responses to isometric, concentric and eccentric contractions of the knee extensors at the same torque-time integral.

PURPOSE: The present study compared isometric, concentric and eccentric contractions at the same torque-time integral for changes in neuromuscular fatigue and muscle damage parameters. METHOD: Healthy men (18-24 years) were placed to either isometric (ISO), concentric (CONC), or eccentric (ECC) group (n = 11/group) that performed corresponding contractions of the knee extensors to exert the same amount of torque-time integral (24,427 ± 291 Nm·s). Changes in maximal voluntary contraction (MVC) torque, voluntary activation, evoked torque at 10 Hz and 100 Hz and its ratio, M-wave amplitude, and muscle soreness were assessed immediately before and after, 1 h, 1 day and 2 days after each exercise, and were compared among the groups. RESULTS: MVC torque decreased immediately after ISO (- 17.0 ± 8.3%), CONC (- 21.7 ± 11.5%) and ECC (- 26.2 ± 15.6%) similarly (p = 0.35), but the decrease sustained longer (p < 0.05) for ECC (2 days post-exercise: - 12.9 ± 14.8%) and ISO (- 5.5 ± 7.9%) than CONC (+ 5.0 ± 11.0%). Muscle soreness developed after ECC (25.1 ± 19.8 mm) and ISO (17.5 ± 21.0 mm) similarly (p = 0.15). Voluntary activation decreased immediately (- 3.7 ± 6.6%) and 1 h post-exercise (- 4.7 ± 7.6%) for all groups similarly. Electrically evoked forces decreased greater immediately (- 30.1 ± 15.6%) and 1 h post-exercise (- 35.0 ± 12.8%) for ECC than others, and the decrease in 10/100 Hz ratio was also greater immediately (- 30.5 ± 12.6%) and 1 h after ECC (- 23.8 ± 10.3%) than others. CONCLUSION: ISO, CONC and ECC with the same torque-time integral produced similar neuromuscular fatigue at immediately post-exercise, but the force loss was longer-lasting after ISO and ECC than CONC, and the changes in peripheral fatigue parameters were the greatest after ECC, suggesting greater muscle damage.

Effect of race distance on performance fatigability in male trail and ultra-trail runners.

The etiology of changes in lower-limb neuromuscular function, especially to the central nervous system, may be affected by exercise duration. Direct evidence is lacking as few studies have directly compared different race distances. This study aimed to investigate the etiology of deficits in neuromuscular function following short versus long trail-running races. Thirty-two male trail runners completed one of five trail-running races as LONG (>100 km) or SHORT (<60 km). Pre- and post-race, maximal voluntary contraction (MVC) torque and evoked responses to electrical nerve stimulation during MVCs and at rest were used to assess voluntary activation and muscle contractile properties of knee-extensor (KE) and plantar-flexor (PF) muscles. Transcranial magnetic stimulation (TMS) was used to assess evoked responses and corticospinal excitability in maximal and submaximal KE contractions. Race distance correlated with KE MVC (ρ = -0.556) and twitch (ρ = -0.521) torque decreases (p ≤ .003). KE twitch torque decreased more in LONG (-28 ± 14%) than SHORT (-14 ± 10%, p = .005); however, KE MVC time × distance interaction was not significant (p = .073). No differences between LONG and SHORT for PF MVC or twitch torque were observed. Maximal voluntary activation decreased similarly in LONG and SHORT in both muscle groups (p ≥ .637). TMS-elicited silent period decreased in LONG (p = .021) but not SHORT (p = .912). Greater muscle contractile property impairment in longer races, not central perturbations, contributed to the correlation between KE MVC loss and race distance. Conversely, PF fatigability was unaffected by race distance.

Sex Differences in Neuromuscular Fatigue and Changes in Cost of Running after Mountain Trail Races of Various Distances.

INTRODUCTION: Women have been shown to experience less neuromuscular fatigue than men in knee extensors (KE) and less peripheral fatigue in plantar flexors (PF) after ultratrail running, but it is unknown if these differences exist for shorter trail running races and whether this may impact running economy. The purpose of this study was to characterize sex differences in fatigability over a range of running distances and to examine possible differences in the postrace alteration of the cost of running (Cr). METHODS: Eighteen pairs of men and women were matched by performance after completing different races ranging from 40 to 171 km, divided into SHORT versus LONG races (<60 and >100 km, respectively). Neuromuscular function and Cr were tested before and after each race. Neuromuscular function was evaluated on both KE and PF with voluntary and evoked contractions using electrical nerve (KE and PF) and transcranial magnetic (KE) stimulation. Oxygen uptake, respiratory exchange ratio, and ventilation were measured on a treadmill and used to calculate Cr. RESULTS: Compared with men, women displayed a smaller decrease in maximal strength in KE (-36% vs -27%, respectively, P < 0.01), independent of race distance. In SHORT only, women displayed less peripheral fatigue in PF compared with men (Δ peak twitch: -10% vs -24%, respectively, P < 0.05). Cr increased similarly in men and women. CONCLUSIONS: Women experience less neuromuscular fatigue than men after both "classic" and "extreme" prolonged running exercises but this does not impact the degradation of the energy Cr.

Reductions in motoneuron excitability during sustained isometric contractions are dependent on stimulus and contraction intensity.

Cervicomedullary stimulation provides a means of assessing motoneuron excitability. Previous studies demonstrated that during low-intensity sustained contractions, small cervicomedullary evoked potentials (CMEPs) conditioned using transcranial magnetic stimulation (TMS-CMEPs) are reduced, whereas large TMS-CMEPs are less affected. As small TMS-CMEPs recruit motoneurons most active during low-intensity contractions whereas large TMS-CMEPs recruit a high proportion of motoneurons inactive during the task, these results suggest that reductions in motoneuron excitability could be dependent on repetitive activation. To further test this hypothesis, this study assessed changes in small and large TMS-CMEPs across low- and high-intensity contractions. Twelve participants performed a sustained isometric contraction of the elbow flexor for 4.5 min at the electromyography (EMG) level associated with 20% maximal voluntary contraction force (MVC; low intensity) and 70% MVC (high intensity). Small and large TMS-CMEPs with amplitudes of ∼15% and ∼50% Mmax at baseline, respectively, were delivered every minute throughout the tasks. Recovery measures were taken at 1-, 2.5- and 4-min postexercise. During the low-intensity trial, small TMS-CMEPs were reduced at 2-4 min (P ≤ 0.049) by up to -10% Mmax, whereas large TMS-CMEPs remained unchanged (P ≥ 0.16). During the high-intensity trial, small and large TMS-CMEPs were reduced at all time points (P < 0.01) by up to -14% and -33% Mmax, respectively, and remained below baseline during all recovery measures (P ≤ 0.02). TMS-CMEPs were unchanged relative to baseline during recovery following the low-intensity trial (P ≥ 0.24). These results provide novel insight into motoneuron excitability during and following sustained contractions at different intensities and suggest that contraction-induced reductions in motoneuron excitability depend on repetitive activation.NEW & NOTEWORTHY This study measured motoneuron excitability using cervicomedullary evoked potentials conditioned using transcranial magnetic stimulation (TMS-CMEPs) of both small and large amplitudes during sustained low- and high-intensity contractions of the elbow flexors. During the low-intensity task, only the small TMS-CMEP was reduced. During the high-intensity task, both small and large TMS-CMEPs were substantially reduced. These results indicate that repetitively active motoneurons are specifically reduced in excitability compared with less active motoneurons in the same pool.

Central fatigue aetiology in prolonged trail running races.

NEW FINDINGS: What is the central question of this study? Are spinal and/or supraspinal perturbations implicated in central fatigue induced in the plantar flexor muscles following prolonged trail running races? What is the main finding and its importance? The study confirmed the presence of central fatigue following various trail running distances from 40 to 170 km. The reduction in the V-wave in conjunction with the lack of change in the H-reflex suggests that a major component of this central fatigue may arise from supraspinal mechanisms in the plantar flexor muscles. ABSTRACT: Trail running races are known to induce considerable impairments in neuromuscular function of which central mechanisms are a substantial component. However, the loci of this central fatigue (i.e. supraspinal and/or spinal) is not well identified. The aim of this study was to better understand central fatigue aetiology induced in the plantar flexor muscles by various trail running distances from 40 to 170 km. Eighteen runners participated in the study and neuromuscular function of their plantar flexors was tested before (PRE) and after (POST) various races during the Ultra-Trail du Mont Blanc. Neuromuscular function was evaluated with voluntary and evoked contractions using electrical tibial nerve stimulation. H-reflex and V-wave responses were also measured during submaximal and maximal voluntary contraction, respectively. Reductions in maximal voluntary contraction torque (-29%; P < 0.001) and voluntary activation level (-12%; P < 0.001) were observed after trail running races. The V-wave was reduced in soleus (-35%; P = 0.003) and gastrocnemius medialis (-28%; P = 0.031), with no changes for the H-reflex in soleus (P = 0.577). The present study confirmed the presence of central fatigue following trail running exercise. The reduction in the V-wave in conjunction with the lack of change in the H-reflex suggests that a major component of this central fatigue may arise from supraspinal mechanisms.

Reliability and agreement of a dynamic quadriceps incremental test for the assessment of neuromuscular function.

The quadriceps-intermittent-fatigue (QIF) test assesses knee extensors strength, endurance and performance fatigability in isometric condition. We aimed to assess reliability and agreement for this test in dynamic conditions and with the use of transcranial magnetic stimulation. On two separate sessions, 20 young adults (25 ± 4 yr, 10 women) performed stages of 100 knee extensors concentric contractions at 120°/s (60° range-of-motion) with 10% increments of the initial maximal concentric torque until exhaustion. Performance fatigability across the test was quantified as maximal isometric and concentric torque loss, and its mechanisms were investigated through the responses to transcranial magnetic and electrical stimulations. Reliability and agreement were assessed using ANOVAs, coefficients of variation (CVs) and intra-class correlation coefficients (ICCs) with 95% CI. Good inter-session reliability and high agreement were found for number of contractions [489 ± 75 vs. 503 ± 95; P = 0.20; ICC = 0.85 (0.66; 0.94); CV = 5% (3; 7)] and total work [11,285 ± 4,932 vs. 11,792 ± 5838 Nm.s; P = 0.20; ICC = 0.95 (0.87; 0.98); CV = 8% (5; 11)]. Poor reliability but high agreement were observed for isometric [-33 ± 6 vs. -31 ± 7%; P = 0.13; ICC = 0.47 (0.05; 0.75); CV = 6% (4;8)] and concentric [-20 ± 11% vs. -19 ± 9%; P = 0.82; ICC = 0.26 (-0.22; 0.63); CV = 9% (6; 12)] torque loss. The dynamic QIF test represents a promising tool for neuromuscular evaluation in isokinetic mode.

Fatigue-induced changes in short-interval intracortical inhibition and the silent period with stimulus intensities evoking maximal versus submaximal responses.

During fatiguing exercise, previous studies have employed transcranial magnetic stimulation (TMS) paradigms eliciting either maximal or submaximal short-interval intracortical inhibition (SICI) and silent period (SP) durations. However, the effect of using either approach on the change in these variables with fatigue is unknown. This study examined the effects of using conditioning stimulus (CS, experiment A) and single-pulse TMS intensities (experiment B) that elicit maximal and submaximal SICI and SP duration (MaxSICI vs. SubmaxSICI in experiment A, MaxSP vs. SubmaxSP in experiment B) on the change in these measures with fatigue. In both experiments, participants performed a 10-min sustained isometric knee-extension contraction at a constant level of EMG, with measurements taken with maximal and submaximal intensities at baseline and every 2.5 min throughout the task. Immediately after the 10-min contraction (i.e., without recovery), responses were also measured at the same absolute force level as at baseline. In experiment A, no change in SICI was observed with either CS intensity throughout the EMG task (P > 0.05). However, an 18% decrease in SICI (i.e., less inhibition) was observed at the same absolute force only with the MaxSICI CS intensity (P < 0.01), with no change in SubmaxSICI (P = 0.72). In experiment B, the magnitude of increase in SP with fatigue was similar for both stimulus intensities (stimulus × time interaction: P = 0.44). These results suggest that CS intensities eliciting maximum SICI are more sensitive in detecting fatigue-induced reductions in SICI, whereas increases in SP are detectable with TMS intensities evoking maximal or submaximal SPs.NEW & NOTEWORTHY This study compared the change in silent period (SP) and short-interval intracortical inhibition (SICI) with conditioning stimulus and single-pulse transcranial magnetic stimulation (TMS) intensities (for SICI and SP, respectively) eliciting maximal and submaximal SICI and SP during fatiguing exercise. The results showed that changes in SICI were only detectable with intensities evoking maximal responses, with no difference between intensities for SP. These findings highlight the importance of maximizing SICI with appropriate intensities before measuring SICI during fatiguing exercise.

Disparate kinetics of change in responses to electrical stimulation at the thoracic and lumbar level during fatiguing isometric knee extension.

The present study compared the fatigue-induced change of matched-amplitude thoracic evoked potential (TMEP) and lumbar evoked potential (LEP) following electrical stimulation. Ten participants performed a 3 × 3 min isometric knee extension contraction separated by 4 min of recovery at the level of EMG required to produce 50% maximal voluntary contraction (MVC) force at baseline. The TMEP and LEP were evoked during the ongoing contraction at baseline and every minute into the fatiguing protocol and during recovery. Both responses were also assessed during a transcranial magnetic stimulation (TMS) evoked silent period to elicit a TMS-TMEP and TMS-LEP to assess responses without the confounding influence of descending drive. The results displayed disparate kinetics of the TMS-TMEP and TMS-LEP throughout the fatiguing protocol. The TMS-TMEP was reduced at all time points during exercise (P < 0.001), whereas the TMS-LEP was reduced at 2 min into set 1 and 1 min into sets 2 and 3 (P ≤ 0.04). TMS-LEPs were higher than the TMS-TMEPs at most time points (P ≤ 0.04). No change was observed in the TMEP or LEP. When evoked during the silent period, the reduction in TMEP is greater than the LEP during fatiguing isometric exercise. The disparate kinetics of change suggest that differential mechanisms are responsible for evoked responses to thoracic and lumbar stimulation. More research is required to identify the mechanisms responsible for the TMEP and LEP before precise inferences can be made on what fatigue-induced changes in these variables reflect.NEW & NOTEWORTHY Assessing spinal excitability using lumbar stimulation when measuring responses in lower limbs has been suggested as an alternative method that could circumvent the issues associated with thoracic stimulation. The present study compared responses to the two types of stimuli throughout a fatiguing protocol and demonstrated that lumbar evoked responses differ substantially from thoracic responses when measured in the absence of voluntary drive. These findings suggest that different mechanisms are responsible for evoked responses to thoracic and lumbar stimuli.

Isolated remethylation disorders: do our treatments benefit patients?

Deficiency of 5,10-methylenetetrahydrofolate reductase (MTHFR), the very rare methionine synthase reductase (CblE) and methionine synthase (CblG) defects, and the recently identified CblD-variant-1 defect are primary remethylation defects characterized by an isolated defect in methionine synthesis without methylmalonic aciduria. The clinical signs are mainly neurological, and hematological signs are seen in CblE, CblG, and CblD-variant-1 defects. Patients with neonatal or early-onset disease exhibit acute neurological distress. Infants and children have unspecific mental retardation, often with acquired microcephaly. Without appropriate therapy, they may experience acute or rapidly progressive neurological deterioration, which may be fatal. Adolescents and adults show normal development or mild developmental delay initially and then experience rapid neurological or behavioral deterioration. A few patients may have signs of subacute combined degeneration of the spinal cord. Adults may be asymptomatic or present with isolated thromboembolism. All patients with suspected remethylation disorders should receive emergency treatment with parenteral administration of hydroxocobalamin and folate supplements combined with betaine orally. The long-term treatment of CblE, CblG, and CblD-variant-1 defects consists of parenterally administered hydroxocobalamin and orally administered folate and betaine supplements, whereas patients with MTHFR deficiency require long-term oral folate and betaine supplements. Long-term oral methionine therapy should also be considered. Early treatment may lead to a favorable outcome with developmental recovery and prevention of further neurological deterioration. In contrast, most late-treated patients have severe and irreversible neuromotor impairments. Hematological abnormalities are easily corrected.

Time-course analysis of mouse serum proteome changes following exposure of the skin to ionizing radiation.

Radiation-induced lesion outcomes of normal tissues are difficult to predict. In particular, radiotherapy or local exposure to a radioactive source by accident can trigger strong injury to the skin. The finding of biomarkers is of fundamental relevance for the prediction of lesion apparition and its evolution, and for the settlement of therapeutic strategies. In order to study radiation-induced cutaneous lesions, we developed a mouse model in which the dorsal skin was selectively exposed to ionizing radiation (IR). 2-D difference gel electrophoresis (2-D DIGE) coupled with MS was used to investigate proteins altered in expression and/or PTM in serum. Proteome changes were monitored from 1 day to 1 month postirradiation, at a dose of 40 Gy, in this specific model developing reproducible clinical symptoms ranging from erythema to skin ulceration with wound healing. About 60 proteins (including some isoforms and likely post-translational variants), representing 20 different proteins, that exhibited significant and reproducible kinetic expression changes, were identified using MS and database searches. Several proteins, down- or up-regulated from day one, could prove to be good candidates to prognosticate the evolution of a skin lesion such as necrosis. In addition, we observed shifts in pI of several spot trains, revealing potential PTM changes, which could also serve as indicators of irradiation or as predictors of lesion severity.

Proteomics of human umbilical vein endothelial cells applied to etoposide-induced apoptosis.

We have undertaken to continue the proteomic study of human umbilical vein endothelial cells (HUVECs) using the combination of 2-DE, automated trypsin digestion, and PMF analysis after MALDI-TOF MS and peptide sequencing using nano LC-ESI-MS/MS. The overall functional characterization of the 162 identified proteins from primary cultures of HUVECs confirms the metabolic capabilities of endothelium and illustrates various cellular functions more related to cell motility and angiogenesis, protein folding, anti-oxidant defenses, signal transduction, proteasome pathway and resistance to apoptosis. In comparison with controls cells, the differential proteomic analysis of HUVECs treated by the pro-apoptotic topoisomerase inhibitor etoposide further revealed the variation of eight proteins, namely, GRP78, GRP94, valosin-containing protein, proteinase inhibitor 9, cofilin, 37-kDa laminin receptor protein, bovine apolipoprotein, and tropomyosin. These data suggest that etoposide-induced apoptosis of human vascular endothelial cells results from the intricate involvement of multiple apoptosis processes including at least the mitochondrial and the ER stress pathways. The presented 2-D pattern and protein database, as well as the data related to apoptosis of HUVECs, are available at http://www.huvec.com.